NEAT1 is a therapeutic target for reversing T-cell exhaustion in bladder cancer
Kun Li1, Lixin Niu2, Xufei Zhang2
1Nuclear Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
Background:
T-cell exhaustion induced by the tumor microenvironment is an important factor in posing a major challenge to effective cancer immunotherapy. Immune checkpoint inhibitors aim to reverse T-cell exhaustion. However, the effectiveness of immune checkpoint inhibitors is often limited due to their off-target effects and single targets. Herein, we attempt to identify molecular targets that can regulate the expression of multiple immune checkpoints to reverse T-cell exhaustion.
Methods:
NSG mice with xenotransplantation of human bladder cancer cells were used to investigate the function of nuclear paraspeckle assembly transcript 1 (NEAT1) in T-cell exhaustion. Chromatin isolation by RNA purification, chromatin immunoprecipitation, and luciferase assays was employed to investigate the molecular mechanisms by which NEAT1 regulates expression of target genes.
Results:
NEAT1, a bladder cancer-related long non-coding RNA (lncRNA), promotes lactate production in tumor cells by binding to the lactate dehydrogenase A gene. This lactate production subsequently inhibits NEAT1 expression in CD8+T cells. Furthermore, NEAT1 in CD8+T cells plays a crucial role in modulating the immune response of CD8+T cells against tumor cells. Our findings indicate that NEAT1 regulates the expression of multiple immune checkpoint genes by directly binding to them and inhibiting transcription through the alteration of histone lactylation near transcriptional start sites, which affects RNA polymerase II recruitment.
Conclusions:
lncRNA NEAT1 serves as a modulator of the antitumor response of CD8+T cells in the bladder tumor microenvironment and may represent a therapeutic target for reversing T-cell exhaustion.
Insights
Nuclear paraspeckle assembly transcript 1 (NEAT1) is a key regulator of T-cell exhaustion in bladder cancer. Targeting NEAT1 could reverse T-cell exhaustion and enhance cancer immunotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- T-cell exhaustion in the tumor microenvironment hinders cancer immunotherapy.
- Current immune checkpoint inhibitors have limitations due to off-target effects and single targets.
- Identifying novel targets to regulate multiple immune checkpoints is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the role of nuclear paraspeckle assembly transcript 1 (NEAT1) in T-cell exhaustion within the bladder tumor microenvironment.
- To identify molecular mechanisms by which NEAT1 influences immune checkpoint gene expression and T-cell function.
Main Methods:
- Utilized a xenotransplantation model of human bladder cancer in NSG mice.
- Employed chromatin isolation by RNA purification, chromatin immunoprecipitation, and luciferase assays.
- Investigated the interaction of NEAT1 with lactate dehydrogenase A and immune checkpoint genes.
Main Results:
- NEAT1, a bladder cancer-associated long non-coding RNA (lncRNA), promotes lactate production in tumor cells.
- Lactate production inhibits NEAT1 expression in CD8+ T cells, impacting their anti-tumor function.
- NEAT1 directly binds to and inhibits the transcription of multiple immune checkpoint genes by altering histone lactylation.
Conclusions:
- lncRNA NEAT1 modulates CD8+ T-cell anti-tumor responses in the bladder tumor microenvironment.
- NEAT1 represents a potential therapeutic target for overcoming T-cell exhaustion in cancer immunotherapy.
- Targeting NEAT1 may enhance the efficacy of cancer treatments by restoring T-cell function.
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